This volume of the Handbook of Neurochemistry and Molecular Neurobiology focuses on neurochemical aspects of schizophrenia. Chapters cover the full range of schizophrenia symptoms and anatomical pathologies from neurochemical and molecular biology perspectives. Topics include changes in neurotransmitter systems, alteration in receptors, neurotransmitter release, genetic factors, protein alterations, and redox dysregulation.

Researchers seeking problems that offer more hope of success often avoid subjects that seem to be difficult to approach experimentally, or subjects for which experimental results are difficult to interpret. The breakdown part of protein turnover in vivo, particularly in nervous tissue, was such a subject in the past - it was difficult to measure and difficult to explore the mechanisms involved. For factors that influence protein metabolism, it was thought that protein content, function, and distribution are controlled only by the synthetic mechanisms that can supply the needed specificity and response to stimuli. The role of breakdown was thought to be only a general metabolic digestion, elimination of excess polypeptides. We now know that the role of breakdown is much more complex: it has multiple functions, it is coupled to turnover, and it can affect protein composition, function, and synthesis. In addition to eliminating abnormal proteins, breakdown has many modulatory functions: it serves to activate and inactivate enzymes, modulate membrane function, alter receptor channel properties, affect transcription and cell cycle, form active peptides, and much more. The hydrolysis of peptide bonds often involves multiple steps, many enzymes, and cycles (such as ubiquination), and often requires the activity of enzyme complexes. Their activation, modification, and inactivation can thus play an important role in biological functions, with numerous families of proteases participating. The specific role of each remains to be elucidated.

The Handbook is intended to be a service to the neuroscience community, to help in finding available and useful information, to point out gaps in our knowledge, and to encourage continued studies. It represents the valuable contributions of the many authors of the chapters and the guidance of the editors and most important, it represents support for research in this discipline. Based on the rapid advances in the years since the second edition

Understanding the biology of brain function is a great challenge and a major goal of modern science. The brain is one of the last great frontiers in science, and the unraveling of its mysteries is comparable in complexity to efforts in space exploration. A fundamental goal of neuroscience is to understand how neurons generate behavior and the pathophysiology of different mental and neurological diseases. The aim of this book is to describe recent discoveries about the basic operations of the brain and to provide an introduction to the adaptations for specific types of information processing.

Stroke is a global health problem affecting approximately 15 million people annually in the world and about 700,000 in the United States. It is the third leading cause of death and the most common cause of disability in most developed countries.

Acute Ischemic Injury and Repair in the Nervous System is intended to provide the most up-to-date knowledge of the mechanisms of neuronal death and repair after stroke. It is our belief that this volume of the Handbook of Neurochemistry and Molecular Neurobiology provides an excellent review of the tremendous advances of the past decades in the neurochemical and molecular biological aspects of cerebral ischemia. It is hoped that these advances will provide an impetus for basic scientists and clinicians to further their translational research and to promote the insights for development of therapeutic interventions for stroke.

This volume is a collection of a variety of brain proteins and peptides whose structures and functions are relatively well known. Each chapter provides a succinct and up-to-date summary of a protein or peptide as well as a review of the individual's contributions to the field. The volume explores the progress that has been made in the field over the past few years and provides insight into the field today.

This volume of the Handbook of Neurochemistry and Molecular Biology focuses on molecular events involved in synapse formation, synaptic plasticity and ongoing neural activity. The volume explores axonal growth cones, synapse development, and mechanisms of LTP and LTD, and calcium dynamics. Particular attention is given to function and trafficking of membrane proteins including various ion channels, aquaporines, gap junctions.

This volume is concerned with the enzymes of the nervous system. Cerebral enzymes form the basis of the functional brain. They are needed for the control of the energetics of the nervous system, whether it be their release or their direction; for the elaboration of transmitters and for their destruction; for the synthesis, transport, and breakdown of all metabolites of the nervous system. They are indispensable for the control of the multitude of factors that govern our thinking and our behavior. They make it possible for us to comprehend what is taking place around us and perhaps to understand what may be in store for us. Enzymes are the stuff of life, and no living cell can be without them. They are the results of many millions of years of evolution, from the time when biological membranes first came into being and were folded to produce the first cells within which the earliest enzymes were wrought. Countless changes have taken place within them, so that, now, only those enzymes exist that play specific roles in the functions of the living cells of today. Those in the nervous system possess a mUltiple role: in the creation, maintenance, and ultimate breakdown of the component cells and in enabling consciousness, perception, memory, and thought to become possible. But though life may go on forever, the enzymes that make life possible will undergo the many changes involved in the evolutionary process.

This volume is concerned with the enzymes of the nervous system. Cerebral enzymes form the basis of the functional brain. They are needed for the control of the energetics of the nervous system, whether it be their release or their direction; for the elaboration of transmitters and for their destruction; for the synthesis, transport, and breakdown of all metabolites of the nervous system. They are indispensable for the control of the multitude of factors that govern our thinking and our behavior. They make it possible for us to comprehend what is taking place around us and perhaps to understand what may be in store for us. Enzymes are the stuff of life, and no living cell can be without them. They are the results of many millions of years of evolution, from the time when biological membranes first came into being and were folded to produce the first cells within which the earliest enzymes were wrought. Countless changes have taken place within them, so that, now, only those enzymes exist that play specific roles in the functions of the living cells of today. Those in the nervous system possess a mUltiple role: in the creation, maintenance, and ultimate breakdown of the component cells and in enabling consciousness, perception, memory, and thought to become possible. But though life may go on forever, the enzymes that make life possible will undergo the many changes involved in the evolutionary process.

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Animals share the challenge of maintaining an internal environment that is restricted to fairly low ranges of temperature, pH, and water content within a well-protected envelope while engaged in continuous exchanges with the environment in terms of gases, liquids, energy, even as movement of body parts and the entire organism itself is necessary for survival. This dynamic spectrum of changes is further amplified during developmental events or more acutely during responses to pernicious environmental factors in due to trauma and disease. In addition, persistent incidents associated with aging can result in irreversible changes to the allostasis that characterizes the living condition.

In the nervous system, a very high metabolic turnover, fragile but steep ionic gradients, and morphological and structural constraints dictated by the necessity for prompt neuronal transmission of electrical impulses and necessary plasticity result in a highly fragile organ system.

Here we address a small sampling of major constituents of neural function at the cellular and molecular level that play important roles in development and aging, two endogenous processes that embody features of allostasis or the dynamic shifts in set points for specific homeostatic mechanisms associated with development and aging.

The opening chapters discuss the major players in the neurotrophic hypothesis, the neurotrophins. These growth factors have been shown to play a significant role during development and in the maintenance of the adult cholinergic system in CNS as well as in the development of the sensory and sympathetic nervous system. That they are also involved in plasticity events associated with memoryand behavior points to the degenerate nature of signaling molecules that archive specificity by acting in concert as part of ensembles of molecules rather than solitary regulators.

It is widely known that oligodendroglia and myelination events are late arrivals in the developmental scheme of the brain and are also prime targets in early development of ischemic insults. Thus, a chapter on oligodendroglia and myelination in development and aging serves to introduce these nonneuronal partners vital to proper neuronal transmission. Molecular participants in stress responses to both acute and chronic stressors are discussed from different perspectives in following chapters with varying degrees of emphasis on injury versus normal aging and neurodegenerative disease.

The study of neural responses to stress of various kinds has led to a realization of the importance of plasticity and the complexity of the mechanism allowing plasticity in the nervous system. The chapters addressing the topic are followed by an introduction to the amyloid hypothesis, and what may be its central character the enzyme held mostly responsible for the generation of beta amyloid. This if followed by a broader discussion of misfolding proteins in the nervous system and its possible interventions to counteract aging-associated deficits.

Limited in scope but offering a broad sampling, these chapters stress the dynamic features of neuronal responses to internal (developmental) cues or the more harmful external events (injury and disease) in a modern perspective.

Contents include: 'Biochemistry and molecular biology of neural lipids', 'Advances in lipid analysis/lipidomics', 'Metabolism and enzymology of glycerolipids', 'Lipid metabolism in brain development and aging', 'Cellular and subcellular localization of neural lipids', and much more.

This volume is concerned with the enzymes of the nervous system. Cerebral enzymes form the basis of the functional brain. They are needed for the control of the energetics of the nervous system, whether it be their release or their direction; for the elaboration of transmitters and for their destruction; for the synthesis, transport, and breakdown of all metabolites of the nervous system. They are indispensable for the control of the multitude of factors that govern our thinking and our behavior. They make it possible for us to comprehend what is taking place around us and perhaps to understand what may be in store for us. Enzymes are the stuff of life, and no living cell can be without them. They are the results of many millions of years of evolution, from the time when biological membranes first came into being and were folded to produce the first cells within which the earliest enzymes were wrought. Countless changes have taken place within them, so that, now, only those enzymes exist that play specific roles in the functions of the living cells of today. Those in the nervous system possess a mUltiple role: in the creation, maintenance, and ultimate breakdown of the component cells and in enabling consciousness, perception, memory, and thought to become possible. But though life may go on forever, the enzymes that make life possible will undergo the many changes involved in the evolutionary process.

That chemicals (although not always called by this name) affect the brain and its functions, such as behavior, has been known for thousands of years. It is therefore surprising that the concept that chemical mechanisms are at least partially responsible for the complex functions of the brain is so recent. Investigation of the closely interlinked biophysical and biochemical proper ties of the nervous system has achieved many notable successes in recent years and is the most exciting development in 20th-century science. Although all the morphology, the activity, and the alteration of the brain, whether bioelectric, biochemical, pathological, or structural, constitute an organic and indivisible whole, the ambition of the Handbook is to look at only a few aspects of this whole and to focus the discussions on the experi ments that the neurochemists have performed. Neurochemical study of the nervous system has, perhaps of necessity, gone through several phases: the first phase was more analytical and in volved study of the composition of the tissue; the second, more recent phase clarified many of the metabolic sequences that occur in this tissue. Clearly, both were essential, but they showed that additional approaches are neces sary. The present phase seems to be the study of control processes; present interest focuses on what determines, in a qualitative and quantitative fashion, the processes occurring in the nervous system. Perhaps the next phase will be the study of function, the study of the final stage of integration.

After the completion of the first edition of this series, this editor thought that a new edition would not be warranted in less than IS, perhaps 20, years, but it seems that we live in a time in which rapid changes are the norm and findings in a field such as neurochemistry develop exponentially. The task of a future editor attempting to get a comprehensive neurochemical handbook for the year 2000 would be even less enviable, but by then information processing may be very different. The approach, the design, and the areas covered by each volume and each chapter are necessarily arbitrary, and it is likely that other editors or authors would have approached the coverage or the organization in a different manner. It is hoped, however, that readers will find the series helpful for beginning or for continuing work. There may be some overlap among the various chapters, but insisting on single coverage of an area would at times have restricted treatment to only one point of view and might have truncated and hurt the logical flow of some of the chapters.

The explosive accumulation of new knowledge in the biological sciences in the last decades has advanced our understanding of the basic mechanisms that underlie most biological phenomena. These advances, however, have not been uniform but have varied considerably among the different biological problems. In some cases, e.g., biochemical genetics, radical advances have been made which have changed our ideas and our approaches. In other cases, even with work which has yielded much detailed new knowledge, our under standing of basic mechanisms remains very inadequate. Among the lines of work that have not yet led to dramatic conceptual advances is the problem of control of biological activities. This problem is, of course, basic both to any full understanding of life as a whole, and to any real understanding of its most minute phenomena. Indeed, the myriad of biological activities that we can observe by direct or indirect means are all under the sway of most exquisitely precise mechanisms. Any malfunctioning of these mechanisms has serious consequences, not only for the particular function itself, but for all the related and interlinked activities."

When the projected volumes of the Handbook are completed, most of our current knowledge of the biochemistry of nervous systems will have been touched upon. A number of the chapters will have dealt with the correlations of the biochemical findings with morphological and physio logical parameters as well. Considering the abysmal lack of such attempts, even in the recent past, this is a sign of great progress. If the reader's eventual goal is to derive the "laws" that relate various aspects of animal and human behavior to underlying physiological and biochemical function, these admirable volumes will help him to establish a firm biochemical base from which to operate. It is certain that the future approaches to the various problems of the information-processing functions of the nervous system will require an integrated understanding of the essence of all of the scientific disciplines which are grouped under the general name of neuro biology. The rich feast of information offered up in this Handbook will enable those in the non-chemical disciplines to pick and choose those areas of chemical information pertinent to their immediate interests. Similar types of compendia by physiologists, anatomists, cyberneticists, and psychologists have been helpful to chemists and continue to be so.

This volume is concerned with metabolic reactions occurring in the nervous system. Some time ago, it was thought that since most of the intermediary metabolism that can be observed in the brain is not specific to this organ, there is little justification in studying neural metabolism as such. Later it was realized that for an understanding of neural functions, the understanding of metabolism in the brain and its alterations is essential. All aspects of the metabolism of a substrate in brain, or all metabolic reactions of the nervous system, could not be included in this volume; some will be dealt with in other volumes (such as the ones covering metabolic turn over, alterations of metabolism, or pathology). Review of the aspects covered here clearly shows that the study of metabolic reactions in the nervous system is a very active field, producing important results. As in so many areas of research, as we learn more, new aspects become known, new questions emerge, and we see that in solving some problems we open areas with many additional problems to solve. But the accomplishments to date are impressive and indicate further important advances in the future. Brain metabolism is more active, more plastic, and more comprehensive than previously estimated. It is an essential part of brain function, and with its alteration, brain function will be altered. This shows the importance of more knowledge in this area. It is hoped that this volume will be of assistance in such further studies."

It has been recognized for more than a thousand years that the function of the brain, like the function of the other organs of the body, is determined by its physical, chemical, and biological properties. Evidence that even its highest functions could be explained by these properties was gathered only in recent years, however; these findings, which clearly have to be confirmed by a great deal of further experimental evidence, indicate that most, if not all, of the functions of the brain are based on its bio chemical and biophysical mechanisms. This at first hearing may sound rather simple, but the ability to understand learning, emotion, perhaps even creativity, on biological terms may well be the most important scientific discovery of all time. Few pieces of knowledge can influence our future health and well-being to the degree that understanding of mental mechanisms will. It has been clearly shown in many ways in the previous volumes of this Handbook that from the biochemical or neurochemical point of view the brain is one of the most active organs. The brain seems stable and in some respects permanent; this is evidence not of inactivity but of carefully controlled homeostasis, of dynamic rather than static equilibrium, with most components undergoing metabolic alterations.

The content of Volume 8 of the Handbook of Neurochemistry is a perfect example and sample of what occupies neurochemists in the late 1980s. What occupies them are questions, concepts, and technology that either did not start with the nervous system, or rapidly moved out of its exclusivity (see, for in- stance, chapters on neurotensin, beta-lipotropin, behavioral and neurochemical effects of ACTH, cholecystokinin, etc.). Thus, the neurochemist is more and more seen as a biochemist occupied by questions, concepts, and technology that are not unique to the nervous system, even though the ultimate substrate of these questions, as well as the ultimate functions so studied and occasionally explained, are of the nervous system. Look at the case of the hypothalamic hypophysiotropic peptides, also called hypothalamic releasing factors, or hypothalamic releasing hormones. These are all small-to-medium-size polypeptides originally characterized in ex- tracts of the hypothalamus on the basis of bioassays directed at studying their effects on one or another of the secretions of the adenohypophysis. We know now that TRFs (See Chapter 8), the thyrotropin and prolactin releasing factor, somatostatin, the hypothalamic inhibitor of the secretion of growth hormone, as well as LRF, the hypothalamic decapeptide stimulating the secretion of pituitary gonadotropins, are to be found in parts of the brain other than the hypothalamus, where their function is obviously not hypophysiotropic. Such is also the case for CRF-the corticotropin and beta-endorphin releasing factor.